Effect of depletion of FOXO3A on gene expression of U-937 cells
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE218289 | GEO | 2023/08/01
REPOSITORIES: GEO
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Project description:Neuroblastoma is a pediatric tumor of the peripheral sympathetic nervous system with a highly variable prognosis. Activation of the PI3K/AKT pathway in neuroblastoma is correlated with poor patient prognosis, but the precise downstream effectors mediating this effect have not been determined. Here, we identify the forkhead transcription factor FOXO3a as a key target of the PI3K/AKT pathway in neuroblastoma. FOXO3a expression was elevated in low stage neuroblastoma tumors and normal embryonal neuroblasts, but reduced in late stage neuroblastoma. Inactivation of FOXO3a by AKT was essential for neuroblastoma cell survival. Treatment of neuroblastoma cells with the dual PI3K/mTOR inhibitor PI-103 activated FOXO3a and triggered apoptosis. This effect was rescued by FOXO3a silencing. Conversely, apoptosis induced by PI-103 or the AKT inhibitor MK-2206 was potentiated by FOXO3a overexpression. Further, levels of total or phosphorylated FOXO3a correlated closely with apoptotic sensitivity to MK-2206. In clinical specimens, there was an inverse relationship between gene expression signatures regulated by PI3K signaling and FOXO3a transcriptional activity. Moreover, high PI3K activity and low FOXO3a activity were each associated with an extremely poor prognosis. Our work indicates that expression of FOXO3a and its targets offer useful prognostic markers as well as biomarkers for PI3K/AKT inhibitor efficacy in neuroblastoma. Affymetrix U133 Plus 2.0 profiling of SY5Y-TetR-FOXO3A cells treated with doxycycline and/or the PI3K/mTOR inhibitor PI-103. Each condition profiled in triplicate.
2013-05-01 | E-GEOD-42762 | biostudies-arrayexpress
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Project description:c-Jun N-terminal kinase (JNK) plays a pivotal role in the regulation of cancer cell apoptosis. Previous studies have revealed that forkhead transcription factor (Foxo3a) is a critical effector of JNK-mediated tumor suppression. However, it is not clear whether caveolin-1 (CAV1) mediated JNK/Foxo3a pathway is involved in cancer cell apoptosis. We found that cordycepin upregulates CAV1 expression, which was accompanied by JNK phosphorylation (p-JNK), which induced Foxo3a translocation into the nucleus, resulting in the upregulation of levels of Bax protein. Furthermore, we found that CAV1 overexpression upregulated p-JNK, whereas siRNA mediated inhibition of CAV1 downregulated p-JNK, and that JNK inhibition by SP600125, a specific JNK inhibitor, significantly increased Foxo3a phosphorylation (p-Foxo3a), which attenuated Foxo3a translocation into the nucleus, indicating caveolin-1 mediated JNK’s regulation of Foxo3a. siRNA mediated inhibition of Foxo3a downregulated levels of Bax protein, attenuated A549 cell apoptosis, indicating that CAV1 mediated JNK/Foxo3a pathway induce the apoptosis of A549 lung cancer cells. Taken, together, these results indicate that cordycepin promotes CAV1 upregulation to enhance JNK/Foxo3a signaling pathway activation to induce apoptosis in lung cancer cells and support the potential of cordycepin as a therapeutic agent for lung cancer.
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Project description:Persistence of memory CD4+ T cells in ECs was coupled with the inactivation of FOXO3a transcriptional activities, which we have previously identified as a critical regulator of TCM survival. Indeed, expression levels of transcriptional targets of FOXO3a, endowed with pro-apoptotic and anti-proliferative functions, were lower in TCM and TEM from ECs as compared to ST individuals. Silencing the transcriptionally active form of FOXO3a by siRNA rescued TCM and TEM of STs from Fas-mediated apoptosis. Moreover the expression of FOXO3a dominant negative form (FOXO3a Nt) rescued the long-term survival of TCM from STs as these cells persisted as long as those derived from ECs. Overall, these studies indicate that FOXO3a activation is an important mediator of the shortened survival and heighteined turnover of TCM and TEM in chronic HIV infection. Targeting this pathway may provide a strategy to preserve memory T cell numbers in HIV infection. Keywords: comparative gene profile, cell-type comparison
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Project description:We employed microarray expression profiling to identify genes which are differentially regulated in the absence of FoxO3a, upon Salmonella typhimurium (ST) infection. ST induced gene expression changes were measured in Wild-type and FoxO3a-/- bone marrow derived macroophages at 6 hours post infection. The array showed an enrichment of MAPK signaling and alterations in inflammatory cytokines and ROS regulators in the absence of FoxO3a. Gene expression changes in bone marrow derived macrophages was measured after infection with 10 MOI of Salmonella typhimurium. Control samples were left untreated. Two mice from each genotype were used for the experiment.
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Project description:We established a model system in human DLD1 colon cancer cells to study the transcriptional crosstalk between FOXO3A and beta-Catenin. Thereby, translocation to the nucleus of a AKT-insensitive mutant (T32A, S253A, S315A) of human FOXO3A fused to the ligand binding domain of human estrogen receptor can be induced by exposure to 4-hydroxy-tamoxifen. Furthermore, expression of a stable mutant (S33Y) of human beta-catenin is doxycycline inducible. Addition of those drugs separately or in combination allows identification of common or excusive target gene sets.
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Project description:Persistence of memory CD4+ T cells in ECs was coupled with the inactivation of FOXO3a transcriptional activities, which we have previously identified as a critical regulator of TCM survival. Indeed, expression levels of transcriptional targets of FOXO3a, endowed with pro-apoptotic and anti-proliferative functions, were lower in TCM and TEM from ECs as compared to ST individuals. Silencing the transcriptionally active form of FOXO3a by siRNA rescued TCM and TEM of STs from Fas-mediated apoptosis. Moreover the expression of FOXO3a dominant negative form (FOXO3a Nt) rescued the long-term survival of TCM from STs as these cells persisted as long as those derived from ECs. Overall, these studies indicate that FOXO3a activation is an important mediator of the shortened survival and heighteined turnover of TCM and TEM in chronic HIV infection. Targeting this pathway may provide a strategy to preserve memory T cell numbers in HIV infection. Keywords: comparative gene profile, cell-type comparison Isolation of CD4+T cell sub-populations. Peripheral blood mononuclear cells (PBMCs) from healthy adult individuals were isolated by Ficoll-HyPaque (Pharmacia) density gradient. We first enriched for CD4+ T cells using negative immunomagnetic beads selection (Automacs, Myltenii), cells were then labeled with anti-CD4-APCcy7, anti-CD45RA-ECD, anti-CD27-FITC and anti-CCR7-PEcy7 and sorted into Naive cells described as CD4+, CD45RA+, CD27+ and CCR7+, Central Memory cells (TCM) described as CD4+, CD45RA-, CD27+ and CCR7+ cells and Effector Memory cells (TEM) described as CD4+, CD45RA-, CD27- and CCR7- cells. Sorting was performed using a BDAria (BD Pharmingen). Purity of the TCM and TEM sub-populations was ranging from 96 to 99%. All procedures were done at 4C to avoid any changes in cell phenotype or gene expression. Sample RNA was extracted using an RNA extraction kit (Quiagen), then amplified using the MessageAmp RNA kit (Ambion) as per the manufacturer’s instructions. The amplified RNA (aRNA) was then verified for quality and quantity using the Agilent Bioanalyser and measuring the OD. Universal human RNA (Stratagene) was also prepared in the same way. Sample probes were prepared by direct labelling with 3 µg of the aRNA Cy-5 (R values) fluorescent dye while the universal RNA probes were prepared by direct labelling of universal aRNA with Cy-3 (G values). All patient samples were hybridized against amplified universal RNA at 37 ºC for 18h on a custom human Immune array. Detailed information on the labeling and hybridization procedures can be obtained at the Microarray Centre web page (University Health Network).
2009-03-03 | E-GEOD-8964 | biostudies-arrayexpress
Project description:The molecular events that are involved in the establishment and the maintenance of CD4+ Central Memory (TCM) and Effector Memory (TEM) T cells are poorly understood. Using global gene expression profiling, single cell proteomics, and functional assays, we show that the survival of TCM CD4+ T cells involves the activation and phosphorylation of STAT5a and FOXO3a. STAT5a phosphorylation induces the transcriptional up-regulation of anti-apoptotic genes specifically in TCM. The phosphorylation of FOXO3a at S315, following TCR engagement, prevents the transcription of pro-apoptotic gene like FasL and BIM. Experiments aimed at blocking FOXO3a phosphorylation confirmed the role of FOXO3a in protecting TCM from apoptosis. Our results define the underlying molecular mechanisms responsible for the longevity and persistence of CD4+ TCM. Keywords: comparative gene profile, cell-type comparison, central memory to Effector memory
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